A cubic porphyrin-based covalent organic framework (COF) named CTP with excellent hydrophilicity was prepared with a facile method for the first time. Different from the conventional methods for the synthesis of porphyrin-based COFs, this facile strategy has greatly shortened the reaction time under mild conditions. Linking the porphyrin monomer into the COF overcame its poor solubility and biocompatibility and also narrowed the band gap owing to the formation of the π-conjugation structure. The improved biocompatibility and narrowed band gap enabled CTP to be an excellent sonosensitizer with an enhanced sonodynamic effect. Moreover, CTP could also effectively realize photothermal conversion under external irradiation due to the extended conjugated structure. This work developed a novel synthesis method for COFs and employed a COF as a sonosensitizer for the first time, which not only provided a new strategy to improve the efficiency of organic sonosensitizers but also inspired us to design more functional COFs for versatile applications.

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Nowadays, Fenton chemistry‐based chemodynamic therapy (CDT) is an emerging approach to killing tumor cells by converting endogenous H2O2 into cytotoxic hydroxyl radicals (·OH). However, the elimination of ·OH by intracellular overexpressed glutathione (GSH) results in unsatisfactory antitumor efficiency. In addition, the single mode of consuming GSH and undesirable drug loading efficiency cannot guarantee the efficient cancer cells killing effect. Herein, a simple one‐step strategy for the construction of Fe3+‐naphthazarin metal–phenolic networks (FNP MPNs) with ultrahigh loading capacity, followed by the modification of NH2‐PEG‐NH2, is developed. The carrier‐free FNP MPNs can be triggered by acid and GSH, and rapidly release naphthazarin and Fe3+, which is further reduced to Fe2+ that exerts Fenton catalytic activity to produce abundant ·OH. Meanwhile, the Michael addition between naphthazarin and GSH can lead to GSH depletion and thus achieve tumor microenvironment (TME)‐triggered enhanced CDT, followed by activating ferroptosis and apoptosis. In addition, the reduced Fe2+ as a T1‐weighted contrast agent endows the FNP MPNs with magnetic resonance imaging (MRI) functionality. Overall, this work is the debut of naphthazarin as ligands to fabricate functional MPNs for effectively depleting GSH, disrupting intracellular redox homeostasis, and enhancing CDT effects, which opens new perspectives on multifunctional MPNs for tumor synergistic therapy.